Publications

Abstract

ackground: Maternal-neonatal listeriosis is a rare and serious infection. The long-term outcome of surviving infants with early-onset or late-onset listeriosis remains unknown. We aimed to determine the long-term neurological and neurodevelopmental outcome of neonatal listeriosis.

Methods: In this prospective, matched, observational cohort study, we evaluated children born with microbiologically confirmed maternal-neonatal listeriosis in the French MONALISA cohort. At age 5 years, children underwent neurological and neurodevelopmental assessments of sensory deficits, executive function, adaptive behaviour, and cognitive and motor coordination function. The cognitive domain was assessed using the French version of the Wechsler Preschool and Primary Scale of Intelligence, fourth edition, and scored by Full Scale Intelligence Quotient (FSIQ). The motor domain was assessed by physical examination designed to screen for cerebral palsy and developmental coordination disorder. Executive functioning was assessed using the statue and inhibition subtests of Neuropsychological Assessment, second version. The sensory domain was assessed by parental interview, medical report, and clinical assessment. Adaptive behaviour was measured using the Vineland-II behaviour scale from parent-reported assessments of functional communication, socialisation, daily living, and motor skills. Results were compared with gestational age-matched children from two national prospective cohorts: EPIPAGE-2 (preterm infants) and ELFE (term infants from a general population of infants >32 weeks gestation). This study is registered with ClinicalTrials.gov (NCT02580812).

Findings: Of 59 children who were alive and eligible to participate in the study, 53 (median age 5 years, IQR 5-6) were enrolled for neurodevelopmental assessments between Oct 26, 2016, and Oct 29, 2019. Of 53 children, 31 (58%) had been born preterm, 22 (42%) had early-onset systemic infection, 18 (34%) had early-onset non-systemic infection, and six (11%) had late-onset systemic infection, all with meningitis. 29 (66%) of 44 children, in whom neurodevelopmental disabilities scores were available, developed at least one disability; eight (18%) children had severe neurodevelopmental disabilities. Of four children with late-onset infection and in whom neurodevelopmental disabilities scores were available, three developed at least one neurodevelopmental disability. Neurological and neurodevelopmental outcomes of children with neonatal listeriosis did not differ from those of gestational age-matched control children without infection (relative risk [RR] of at least one disability 0·99 [95% CI 0·65-1·51; p=0·97]; RR of FSIQ less than -1 SD 0·92 [0·54-1·54; p=0·74]).

Interpretation: These results highlight the burden of persistent disability and dominant contribution of prematurity to long-term outcomes in children born with neonatal listeriosis. The findings support the implementation of systematic long-term screening and provision of tailored education and special needs support.

Abstract

Management of respiratory distress (RD) in the extremely preterm newborn meets recommendations. Few data are available concerning the management and the clinical course of moderate and late preterms with RD. Clinical course and management among moderate (30-33 weeks (wks) of gestation) and late preterms (34-36 wks) were assessed in the Neobs study, a French neonatal observational cohort study (2018) of preterms with RD in the first 24 h of life. Clinical course was defined as stable (use of non-invasive ventilation (NIV) only), initially severe (initial use of invasive ventilation (IV)), and worsening (switch off IV after NIV support). Surfactant therapy instillation and withdrawal of all ventilator support at 72 h were recorded. Among moderate (n = 279) and late (n = 281) preterms, the clinical course was similar (p < 0.27): stable (82.1 and 86.8%), worsening (11.8% and 9.3%), and initially severe RD (6.1% and 3.9%), respectively. Surfactant was administered more frequently in the moderate versus late preterm groups (28.3% vs 16.7%; p < 0.001). The recommended surfactant dose (200 mg/kg) was administered in 53.3-83.3% of moderate and 42.1-63.2% of late preterms according to the clinical course. Withdrawal of ventilatory support at 72 h was observed in 40.0% and 70.0% of moderate and late preterms, respectively (p < 0.05), and was significantly (p < 0.001) associated with clinical course (the minus proportion among the worsening group).

Conclusion: While the proportion of clinical course pattern is similar in moderate and late preterm infants, the management of RD varies with gestational age, with late preterm infants being managed later in life and moderate premature infants weaned from ventilation at a later stage.

What is known: • There is a lack of clear guidance on the management of respiratory distress (RD) in moderate-to-late preterm infants. • Neobs was a multicentre, observational study designed to characterise the real-world management of moderate-to-late preterm infants with RD in France.

What is new: • Secondary analyses of Neobs study data found that ventilatory support strategies were dependent on gestational age despite a similar clinical course. • At 30-33 weeks of gestation (wks), infants were more likely to receive non-invasive ventilation at delivery, while 34-36 wks infants were more likely to be managed using a wait-and-see approach.

Abstract

Background: The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting.

Objective: This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age.

Study design: We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks’ gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks’ gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes.

Results: Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55-1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65-1.61), or any of the other outcomes.

Conclusion: There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

Abstract

Background: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case-control prospective multicenter study.

Methods: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S rRNA gene sequencing was performed on stool samples (n = 103). Specific culture media were used to isolate Escherichia coli, Clostridium butyricum, and Clostridium neonatale, and strains were phenotypically characterized.

Results: The gut microbiota of PNs was dominated by Firmicutes and Proteobacteria, and five enterotypes were identified. The microbiota composition was similar between NEC cases and PN controls. However, differences were observed in the relative abundance of Lactobacillus genus, which was significantly lower in the NEC group, whereas that of the Clostridium cluster III was significantly higher (p < 0.05). Within enterotypes, several phylotypes were significantly more abundant in NEC cases (p < 0.05). Regarding perinatal factors, a statistical association was found between the gut microbiota and cesarean delivery and antifungal therapy. In NEC cases and PN controls, the carriage rates and virulence genes of uropathogenic E. coli were equivalent based on culture. No correlation was found between E. coli, C. butyricum, and C. neonatale carriages, beta-lactam resistance, and antibiotic treatment.

Conclusions: At disease onset, our data support a microbiota dysbiosis between NEC and control infants at the genus level. In addition, it provides valuable information on bacterial antimicrobial susceptibility.

Abstract

To determine the early factors associated with continuous positive airway pressure (CPAP) failure in moderate-to-late preterm infants (32 + 0/7 to 36 + 6/7 weeks’ gestation) from the NEOBS cohort study. The NEOBS study was a multi-center, prospective, observational study in 46 neonatal intensive care units in France, which included preterm and late preterm infants with early neonatal respiratory distress. This analysis included a subset of the NEOBS population who had respiratory distress and required ventilatory support with CPAP within the first 24 h of life. CPAP failure was defined as the need for tracheal intubation within 72 h of CPAP initiation. Maternal and neonatal clinical parameters in the delivery room and clinical data at 3 h of life were analyzed. CPAP failure occurred in 45/375 infants (12%), and compared with infants with CPAP success, they were mostly singletons (82.2% vs. 62.1%; p < 0.01), had a lower Apgar score at 10 min of life (9.1 ± 1.3 vs. 9.6 ± 0.8; p = 0.02), and required a higher fraction of inspired oxygen (FiO₂; 34.4 ± 15.9% vs. 22.8 ± 4.1%; p < 0.0001) and a higher FiO₂*positive end-expiratory pressure (PEEP) (1.8 ± 0.9 vs. 1.1 ± 0.3; p < 0.0001) at 3 h. FiO₂ value of 0.23 (R² = 0.73) and FiO₂*PEEP of 1.50 (R² = 0.75) best predicted CPAP failure. The risk of respiratory distress and early CPAP failure decreased 0.7 times per 1-week increase in gestational age and increased 1.7 times with every one-point decrease in Apgar score at 10 min and 19 times with FiO₂*PEEP > 1.50 (vs. ≤ 1.50) at 3 h (R² of the overall model = 0.83). Conclusion: In moderate-to-late preterm infants, the combination of singleton pregnancy, lower Apgar score at 10 min, and FiO₂*PEEP > 1.50 at 3 h can predict early CPAP failure with increased accuracy. What is Known: •Respiratory distress syndrome (RSD) represents an unmet medical need in moderate-to-late preterm births and is commonly treated with continuous positive airway pressure (CPAP) to reduce mortality and the need for additional ventilatory support. • Optimal management of RSD is yet to be established, with several studies suggesting that identification of predictive factors for CPAP failure can aid in the prompt treatment of infants likely to experience this failure. What is New: •Secondary analysis of the observational NEOBS study indicated that oxygen requirements during CPAP therapy, especially the product of fraction of inspired oxygen (FiO2) and positive end-expiratory pressure (PEEP), are important factors associated with early CPAP failure in moderate-to-late term preterm infants. •The combination of a singleton pregnancy, low Apgar score at 10 minutes, and high FiO2*PEEP at 3 hours can predict early CPAP failure with increased accuracy, highlighting important areas for future research into the prevention of CPAP failure.

No abstract available.

Abstract

The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance.

Abstract

Background: The skin is the largest organ in the human body. It provides multiple barrier functions, tactile or defensive, and acts as a mediator allowing for the attachment of vital monitoring devices with medical adhesives. Adhesives consist of several layers with varying compositions and properties. We aimed to provide recommendations for their use in the care of hospitalized neonates on the basis of a systematic literature review.

Methods: We searched PubMed for English or French articles published before May 29, 2020, using the keywords « adhesive, » « tape, », « skin, » and « neonat*. » Recommendations were developed after review by a multidisciplinary group including 15 professionals and parent representatives.

Results: We identified 295 studies, and from 30 eligible studies we developed six recommendations according to four perspectives: assessment of the skin condition to improve the methods of application of the different adhesives and their removal; use of adhesives as a platform; and discouraging the regular use of semi-permeable dressings to compensate for the immaturity of the skin barrier.

Conclusion: Skin lesions are common for hospitalized neonates. Use of adhesives may increase the occurrence of such lesions. Adhesives should be subject to good clinical practice guidelines. Health professionals caring for newborns should know the tools for screening and preventing skin lesions.

Abstract

Objective: To develop and validate a clinical prediction model for outcomes at 5 years of age for children born extremely preterm and receiving active perinatal management.

Design: The EPIPAGE-2 national prospective cohort.

Setting: France, 2011.

Population: Live-born neonates between 24⁺⁰ and 26⁺⁶ weeks of gestation who received active perinatal management (i.e. birth in a tertiary-level hospital, with antenatal steroids and resuscitation at birth).

Methods: A prediction model using logistic modelling, including gestational age, small-for gestational-age (SGA) status and sex, was developed. Model performance was assessed through calibration and discrimination, with bootstrap internal validation.

Main outcome measures: Survival without moderate or severe neurodevelopmental disability (NDD) at 5 years.

Results: Among the 557 neonates included, 401 (72%) survived to 5 years, of which 59% survived without NDD (95% CI 54% to 63%). Predicted rates of survival without NDD ranged from 45% (95% CI 33% to 57%), to 56% (95% CI 49% to 64%) to 64% (95% CI 57% to 70%) for neonates born at 24, 25 and 26 weeks of gestation, respectively. Predicted rates of survival without NDD were 47% (95% CI 18% to 76%) and 62% (95% CI 49% to 76%) for SGA and non-SGA children, respectively. The model showed good calibration (calibration slope 0.85, 95% CI 0.54 to 1.16; calibration-in-the-large -0.0123, 95% CI -0.25 to 0.23) and modest discrimination (C-index 0.59, 95% CI 0.53 to 0.65).

Conclusions: A simple prediction model using three factors easily known antenatally may help doctors and families in their decision-making for extremely preterm neonates receiving active perinatal management.

No abstract available